Project Summary Identifying neural circuits underlying appetite, such as eating and drinking is critical for understanding brain function and associated disorders such as bulimia, anorexia, or polydipsia. Despite the expanding number of people suffering from appetite disorders, no fundamental treatments are currently available due to the lack of knowledge how appetite is controlled by the brain. Filling this gap is urgent for better understanding of normal as well as abnormal brain functions regulating appetite. The long term goal of this research is to elucidate the mechanisms by which the brain detects internal state, process that information, and drive goal-oriented behaviors. Toward this goal, we recently identified two genetically-defined neural populations in one of brain osmosensory organs, the subfornical organ (SFO), that regulate water drinking in two opposite directions; driving and suppressing thirst. While these regions have long been viewed as just sensors of the brain, recent studies suggest that brain osmosensory organs are also regulated by external sensory or behavioral cues. The hypothesis in this project is that brain sensory organs function as an integrator of internal need and reward signals that optimizes appetite and consummatory behavior. This hypothesis will be tested by four specific aims: 1) visualize brain osmosensory neurons in vivo, and investigate how they are regulated by reward- related cues and behaviors, 2) dissect functionally distinct efferent projections and 3) genetically- defined downstream neurons of the SFO that process thirst in the brain, and 4) determine the neural circuits mediating reward-appetite interaction at the brain osmoensory site. This proposal is innovative, in our opinion, because it applies state-of-the-art manipulation/imaging techniques to establish a novel concept of appetite regulation by dissecting circuits from functionally-defined osmosensory neural populations. This research is significant because it addresses the mechanisms underlying thirst, one of the most fundamental instincts for survival. The successful outcome of this project is expected to advance our understanding of neural basis of appetite regulation, which has the potential to provide key insights into the development of novel treatments for appetite disorders.